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Page 2 Brault et al. J Transl Genet Genom. 2025;9:1-10 https://dx.doi.org/10.20517/jtgg.2024.83

INTRODUCTION
Barth syndrome
Barth syndrome (BTHS; OMIM #302060) is a rare X-linked disorder affecting mainly males and is caused
by mutations in the phospholipid-lysophospholipid TAFAZZIN transacylase (HGNC:11577) gene . The
[1]
Tafazzin protein is mitochondrially located and plays an important role in both mitochondrial formation
and function . BTHS is characterized by dilated cardiomyopathy, neutropenia, growth restriction, growth
[2]
[3-7]
delay, and skeletal myopathy . As with most mitochondriopathies, there is no cure for BTHS, and patients
often succumb to premature death. BTHS patient mortality is thought to be primarily due to
[3,7]
cardiomyopathy, which can progress to heart failure and arrythmias . Additionally, BTHS skeletal
myopathy is detectable from birth and causes low muscle tone (hypotonia), as well as muscle weakness
leading to motor skill delay (crawling, walking) . BTHS boys and men exhibit muscle weakness, extreme
[8]
fatigue during strenuous physical activity, and eating difficulties [8-11] . Despite myopathy being a cardinal
feature of BTHS and mitochondrial dysfunction being well described in BTHS, very little is known about
[12]
the bioenergetic state of muscle in BTHS. Relevant to this literature review, BTHS animal models are
considered models for defective mitochondrial ATP production and, thus, for understanding energy
deficits.

Bioenergetics of ATP
The transfer of energy is central to cell survival. Arguably, the most important intracellular energetic
intermediate is ATP . This is due, at least in part, to the direct transfer of energy from ATP hydrolysis to
[13]
drive essential cellular functions such as protein synthesis and degradation, active ion transport, and muscle
contractions. The amount of available energy from ATP hydrolysis (DG ) is defined by the Gibb’s free
ATP
energy equation:

where DG° is the free energy of ATP hydrolysis under standard conditions of temperature, pressure, and
ATP
substrate/product concentrations in solution, R is the gas constant, and T is the temperature in °K . An
[14]
important aspect of this is that the amount of available energy does not depend solely on the concentration
of ATP but, instead, is dependent on the ratio of the ATP to ADP and inorganic phosphate (Pi). Said
another way, ATP alone is not a sensitive measure of energetic state nor of mitochondrial function .
[15]
In extracts from non-contracting skeletal muscle, consensus levels for total ATP are ~5-6 mmol/g, for ADP
~0.5 mmol/g, and for AMP ~0.1 mmol/g, although values differ between muscles with different fiber
types [16,17] . During periods of substantial energy supply/demand mismatch, such as initial stages of intense
contractions or hypoxia, ATP changes little while ADP and especially AMP increase substantially in part
because of buffering by the near-equilibrium creatine kinase (PCr + ADP ↔ Cr + ATP) and adenylate
kinase (ADP + ADP ↔ ATP + AMP) reactions. Prolonged mismatch between energy supply and demand
would lead to continuous ATP decline and cell death.

When steady-state changes in ATP are detected, results could be interpreted in two ways. First, a reduction
in ATP with an increase in the degradation products ADP, AMP and/or IMP is an indication of severe and/
or prolonged mismatch in ATP supply and demand . This can occur with intense muscle contractions [17,19]
[18]
or hypoxia . Second, decreases in ATP with a concomitant decrease in ADP and AMP, i.e., a decrease in
[20]
the total pool of adenine nucleotides (ATP + ADP + AMP), is an indication of a cellular or phenotypic
change without a mismatch in energy supply and demand. As examples of ATP differences without